Nordihydroguaiaretic acid (NDGA, 1) is a lignan found in the leaves and twigs of the shrub Larrea tridentata. Being a lipoxygenases inhibitor, NDGA can induce cystic nephropathy in the rat.1 In addition, it shows various bioactivities, including inhibition of protein kinase C,2 induction of apoptosis,3 alterations of membrane,4 elevation of cellular Ca2+ level5 and activation of Ca2+ channels in smooth muscle cells,6 breakdown of pre-formed Alzheimer's beta-amyloid fibrils in vitro,7 anti-oxidation,8 etc. This natural product is used commercially as a food additive to preserve fats and butter in some parts of the world. Recently, the derivatives of the plant lignan NDGA have been used to block viral replication through the inhibition of viral transcription.9-16 These compounds can inhibit production of HIV,9-13 herpes simplex virus,14-15 and HPV transcripts16 by deactivation of their Sp1-dependent promoters. Moreover, (tetra-O-methyl)nordihydroguaiaretic acid (M4N, EM1421 2) can function as an anti-HIV proviral transcription inhibitor and causes growth arrest of a variety of transformed human and mouse cells in culture and in mice.17,18,22 Compound M4N (EM1421) is currently in clinical trials against human cancers.23 
While M4N (2) is a strikingly effective and non-toxic anticancer agent, M4N and several other methylated NDGAs, all show poor water solubility which somewhat limit their applicabilities for certain drug action studies. To circumvent this problem, a water soluble derivative of NDGA, (tetra-O-dimethylglycyl)nordihydroguaiaretic acid (G4N, 4) has been designed and synthesized.11 G4N is a very effective mutation-insensitive inhibitor to HIV-1, HSV-1 and HSV-2.10,15 However, it is somewhat unstable and has a relatively short half-life in aqueous solution, reportedly due to the ester bonds connecting the dimethyl glycine moieties onto the NDGA main skeleton.11

Therefore, there is a need for NDGA derivatives with improved water solubility and stability having the desired pharmaceutical effects. Accordingly, we have developed new derivatives of NDGA that have these advantages and will be useful in therapeutic compositions and treatment methods. We describe herein the chemical synthesis of these new compounds and their efficacies.